Role of SPA-1 in Phenotypes of Chronic Myelogenous Leukemia Induced by BCR-ABL–Expressing Hematopoietic Progenitors in a Mouse Model

Kometani, Kohei; Aoki, Masamitsu; Kawamata, Shin; Shinozuka, Yoriko; Era, Takumi; Hattori, Masao; Minato, Nagahiro

doi:10.1158/0008-5472.can-06-1346

Cited by 21 publications

(15 citation statements)

References 46 publications

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“…Previous studies showed that the majority of the Sipa1 2/2 mice and 15% Sipa1 1/2 mice developed CML-like MPN. 15,25 We here observed MDS-like MPN mainly in the aged Sipa1 2/2 female mice. This discrepancy in the observed disease phenotype might be due to different genetic background of the mice.…”

Section: Discussionsupporting

confidence: 49%

Sipa1 deficiency–induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm

et al. 2018

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Key Points• Sipa1 loss leads to BM niche alterations prior to the initiation of MPN.• Sipa1-deficient BM niche induces lethal MPN from normal hematopoietic cells.Mutations of signal-induced proliferation-associated gene 1 (SIPA1), a RAP1 GTPaseactivating protein, were reported in patients with juvenile myelomonocytic leukemia, a childhood myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Sipa1 deficiency in mice leads to the development of age-dependent MPN. However, Sipa1 expression in bone marrow (BM) microenvironment and its effect on the pathogenesis of MPN remain unclear.We here report that Sipa1 is expressed in human and mouse BM stromal cells and downregulated in these cells from patients with MPN or MDS/MPN at diagnosis. By using the

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Section: Discussionsupporting

confidence: 49%

Sipa1 deficiency–induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm

et al. 2018

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“…Indeed, AQP2 trafficking to the apical membrane is impaired in the collecting duct principal cells of SPA-1-deficient mice [68]. SPA-1-deficient mice show marked bilateral hydronephrosis due to polyuria [43,68].…”

Section: Exocytosismentioning

confidence: 99%

The role of actin remodeling in the trafficking of intracellular vesicles, transporters, and channels: focusing on aquaporin-2

Noda

Sasaki

2007

Pflugers Arch - Eur J Physiol

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Trafficking of the intracellular vesicles and membrane protein incorporated in the vesicles is essential for a variety of basic biological processes. Growing evidence has highlighted the importance of the actin cytoskeleton in the trafficking of synaptic vesicles, secretory granules, transporters, and channels including aquaporin. These trafficking processes require actin remodeling, which is spatiotemporally regulated. Recent researches have come to focus on the motility mechanism of the translocation. In this review, we describe the role of actin at each step of intracellular reservation, exocytosis, docking, fusion with the plasma membrane, and endocytosis, focusing on aquaporin-2 trafficking.

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“…7 We also reported that human bcr-abl fusion gene product (Bcr-Abl) was a potent Rap1 activator, 8 and that Bcr-Abl ϩ SPA-1 Ϫ/Ϫ HPCs showed aggravated chronic myelogenous leukemia phenotypes compared with Bcr-Abl ϩ wild-type HPCs in a mouse model, including prolonged survival of leukemic progenitors and rapid blast crisis in vivo. 9 Thus, proto-oncogenes capable of activating Rap1 signal may be potential collaborative factors for leukemia in SPA-1 deficiency.…”

Section: Introductionmentioning

confidence: 99%

Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling

Wang

Aoki

Nakashima

et al. 2008

Blood

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IntroductionRap1, a Ras-family G protein, mediates diverse functions that are highly dependent on the contexts of the cell types, such as proliferation, differentiation, cell survival, cell adhesion, polarity, and movements. 1,2 Rap1 is activated to Rap1GTP by specific guanine nucleotide exchange factors (GEFs) coupled with diverse receptors, whereas specific GTPase-activating proteins (GAPs) hydrolyze Rap1GTP to Rap1GDP. 3 We previously reported that mice deficient for SPA-1, a principal Rap1GAP in hematopoietic progenitor cells (HPCs), developed a spectrum of myeloid leukemia or B1-cell leukemia of long latency. 4,5 The majority of myeloid leukemia in SPA-1 Ϫ/Ϫ mice resembled human chronic myelogenous leukemia and often was associated with blast crisis of myeloid, erythroid, or B-cell lineage, which strongly suggested a disorder of multipotent HPCs. 6 Although the results suggested that SPA-1 functioned as a leukemia suppressor in HPCs, the long latency implied that additional factors might be needed for development of overt leukemia. On the other hand, a Rap1GEF, CalDAG-GEF1, has been reported as a proto-oncogene in BXH-2 myeloid leukemia. 7 We also reported that human bcr-abl fusion gene product (Bcr-Abl) was a potent Rap1 activator, 8 and that Bcr-Abl ϩ SPA-1 Ϫ/Ϫ HPCs showed aggravated chronic myelogenous leukemia phenotypes compared with Bcr-Abl ϩ wild-type HPCs in a mouse model, including prolonged survival of leukemic progenitors and rapid blast crisis in vivo. 9 Thus, proto-oncogenes capable of activating Rap1 signal may be potential collaborative factors for leukemia in SPA-1 deficiency.In the present study, we investigated the effects of C3G expression in normal and SPA-1 Ϫ/Ϫ HPCs in vivo. C3G is a ubiquitous Rap1GEF translocated to the plasma membrane by a wide variety of signals via Crk-family adaptor proteins. 10,11 Farnesylated C3G (C3G-F) shows facilitated recruitment to the plasma membrane to activate endogenous Rap1, 10 although the activity can be counteracted by SPA-1. 12 Results showed that transplantation of normal HPCs expressing C3G-F resulted in a marked expansion of blastic thymocytes with unusual phenotypes, namely, CD4/CD8 double-positive (DP) CD3/TCR␤ Ϫ , in the irradiated recipients. SPA-1 Ϫ/Ϫ HPCs expressing C3G-F caused a more aggressive thymic DP cell expansion with higher levels of Rap1 activation than C3G-F ϩ wild-type HPCs, eventually resulting in lethal T-cell acute lymphoblastic leukemia (T-ALL). Leukemic C3G-F ϩ thymocytes exhibited markedly augmented expression of Notch and the target genes. Furthermore, all the clonal C3G-F ϩ SPA-1 Ϫ/Ϫ T-ALL cell lines revealed characteristic mutations in Notch1, resulting in C-terminal truncation, which is similar to mutations reported in the majority of T-ALL in humans as well as in genetically predisposed animal models. [13][14][15][16] The proliferation was completely inhibited in the presence of a ␥-secretase inhibitor. The current results suggest a functional cross talk of endogenous Rap1 G protein and Notch signaling in thymocyte d...

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Role of SPA-1 in Phenotypes of Chronic Myelogenous Leukemia Induced by BCR-ABL–Expressing Hematopoietic Progenitors in a Mouse Model

Abstract: SPA-1 is a negative regulator of Rap1 signal in hematopoietic cells, and SPA-1-deficient mice develop myeloproliferative disorders (MPD) of long latency. In the present study, we showed that the MPDs in SPA-1

Cited by 21 publications

References 46 publications

Sipa1 deficiency–induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm

Sipa1 deficiency–induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm

The role of actin remodeling in the trafficking of intracellular vesicles, transporters, and channels: focusing on aquaporin-2

Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling

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